AU2002356936A1 - Acetaminophen compositions - Google Patents

Description

WO 03/045305 PCT/US02/36398 ACETAMINOPHEN COMPOSITIONS Field of the Invention The present invention relates to pharmaceutical compositions comprising acetaminophen as the active ingredient. In particular, the invention pertains to acetaminophen compositions having improved solubility characteristics for 5 encapsulation. Background of the Invention Soft gelatin capsules or softgels are predominantly used to contain liquids wherein the active ingredients are present in the dissolved or suspended state. Filled 10 one-piece softgels have been widely known and used for many years and for a variety of purposes. Because softgels have properties that are quite different from telescoping two-piece, hard shell capsules, the softgels are capable of retaining a liquid fill material. Softgels are often used to encapsulate consumable materials, including vitamins, dietary supplements, pharmaceuticals, and the like, in a liquid 15 vehicle or carrier. A particularly good bioavailability of a pharmacologically active substance is attained if the active substance is successfully dissolved in a suitable solvent and the encapsulated solution is administered to the patient. Producing highly concentrated solutions of any acidic, amphoteric or basic pharmaceutical compound is useful 1 WO 03/045305 PCT/USO2/36398 because it permits encapsulation in a softgel capsule of a unit dose which is small enough to permit easy swallowing. Filling a unit dose in a small softgel capsule to permit easy swallowing is useful because it increases patient acceptance of the medication. Patient acceptance of a medication is important because it is a substantial 5 step towards solving the problem of patient noncompliance with the prescribed regimunen. Another utility of highly concentrated solutions is enhancement of bioavailability of the dissolved pharmaceutical compound or composition. Enhanced bioavailability occurs as a result of delivering the pharmaceutical already in solution 10 at the site of absorption, thereby permitting faster and more uniform absorption to occur. One problem associated with such compositions is that obtaining an appropriate solution of the pharmaceutical composition is sometimes difficult. Often it is not possible to dissolve the pharmaceutical compound in a volume of solvent 15 small enough to produce a softgel which is appropriate in size from the standpoint of economics and patient acceptance. Furthermore, the solvent, carrier or vehicle itself must have sufficient solvating power to dissolve the desired amount of the pharmaceutical compound to produce a highly concentrated solution, while at the same time not hydrolyzing, dissolving or discoloring the capsule shell. 20 One approach to achieve this desired goal has been the use of enhanced solubility systems such as those described in Yu et al. U.S. Patent No. 5,071,643. Yu et al. disclose soft gelatin capsules containing highly concentrated acetaminophen 2 WO 03/045305 PCT/USO2/36398 solutions comprising 25-40% by weight acetaminophen, hydroxide ions (e.g., potassium hydroxide), water, and polyethylene glycol. However, hydroxide ion sources at levels required to solubilize acetaminophen increase the pH of the solution to the extent that degradation of the softgel capsule occurs. 5 Other approaches to enhance the solubility of acetaminophen have been used as well. Shelley et al. U.S. Patent No. 5,505,961 describes a method of increasing the solubility of acetaminophen alone or in combination with antihistamines, antitussives, desongestants, and expectorants to form clear solutions for encapsulation in softgel capsules. Shelley et al. teach compositions comprising acetaminophen, potassium or 10 sodium acetate, polyethylene glycol and polyvinyl pyrrolidone which pennits a 325 mg dose to be administered in the same size softgel as a 250 mg dosage product. The capsule sizes needed for a desired dose of these formulations, however, are still relatively large. Another drawback is that the acetate solvent system restricts the amount of other active compounds which can be used due to solubility limitations. 15 Furthermore, the presence of acetate can adversely affect tolerance of certain analgesics. There exists a need for improved softgel formulations containing pharmaceutical compounds such as acetaminophen which permit high concentrations of the drug to be solubilized in lower fill volumes thereby permitting the desired 20 effective dose of drug to be administered to a patient using smaller capsule sizes. 3 WO 03/045305 PCT/USO2/36398 Summary of the Invention The invention herein provides for an oral pharmaceutical composition for use in capsular dosage forms comprising acetaminophen and lactate salts alone or in combination with acetate salts which exhibit improved solubility characteristics of the 5 active ingredient while at the same time permitting the use of smaller capsule sizes to deliver effective doses thereof. In a preferred composition, the combination of 1 lactate (levos) and acetate salts are used in the composition. Furthermore, compositions have improved visual characteristics, e.g., clarity of appearance. The invention also provides for a capsular dosage form, such as a soft or hard gelatin 10 capsule, containing such a composition. Acetaminophen is difficult to dose in a solubilized form due to high therapeutic dose requirements (typically 500 to 1,000 mg) while still using a relatively small appropriate capsule size for patient compliance. It has been discovered that combinations of particular ingredients when used in conjunction with acetaminophen 15 in a liquid fill composition, not only improve the solubility of the acetaminophen thereby permitting increased concentrations of the active ingredient for a given fill, but also improves the appearance of the fill composition as well by way of reduced observable crystallization. In particular, certain combinations of acetaminophen and solvent system comprising lactate salts alone, or both lactate salts and acetate salts, 20 provide such improvements while at the same time provide formulations compatible with capsular encasing materials, such as gelatin. 4 WO 03/045305 PCT/USO2/36398 In one aspect, the invention provides for a liquid oral pharmaceutical composition adapted for use in capsular dosage forms comprising acetaminophen as an active ingredient and a solvent system comprising an alkali metal lactate salt. Preferred alkali metal lactate salts are alkali metal 1-lactate salts. Even more preferred 5 as the alkali metal lactate salt is sodium 1-lactate. The lactate salt can be used alone as the carboxylate salt, or preferably, together with an alkali metal acetate salt. When the combination is used, the preferred acetate salt is potassium acetate. The solvent system of the composition of the invention can further comprise polyethylene glycol and polyvinyl pyrrolidone. 10 Another aspect of the invention provides for a capsular dosage form containing a liquid pharmaceutical composition comprising acetaminophen as an active ingredient and a lactate salt, preferably a 1-lactate salt. Suitable capsular dosage forms include, but are not limited to, capsule casings composed of gelatin, such as soft or hard gelatin. 15 One advantage of the invention is that concentrations of acetaminophen greater than about 40% by weight, and even about 42%, can be achieved per given volume, while still maintaining clarity of appearance of the composition. Furthermore, the composition is suitable for use in capsular materials subject to degradation, such as gelatin. For a given dosage size such as 325 mg, acetaminophen 20 can be present in an amount of about 42% by weight of the fill composition. Accordingly, smaller capsule sizes and/or fewer capsules need to be used to deliver the same effective dose. 5 WO 03/045305 PCT/USO2/36398 Detailed Description of the Invention As used herein, the general term "capsule" is intended to encompass any suitable one-piece capsular containment adapted for oral ingestion and which is 5 adapted for use in conjunction with liquid fill compositions. The term includes capsules having casings composed of soft and hard materials, such as gelatin, starches, celluloses, hydrocolloids, gums, carageegans, or any other natural or synthetic material which can be used to encapsulate the liquid composition and be ingested by an animal. The term is intended to include a variety of capsule shapes 10 and sizes, and is not intended to limit the dosage form to a specific type or shape. The term "acetaminophen" as used herein is intended to include the chemical derivatives of the acetaminophen structure having equivalent pharmaceutical effect. The invention generally includes a liquid oral pharmaceutical composition adapted for use in capsular dosage forms. Specifically, the capsular dosage forms 15 suitable for use with the invention are those which are adapted to contain liquid fill compositions. A variety of capsule casing materials can be used in conjunction with the invention, providing they permit one-piece integrated molding manufacturing techniques. Examples of suitable casing materials include, but are not limited to, gelatin (soft and hard), starches, celluloses, carageegans, hydrocolloids, gums, and the 20 like. Casing materials can be prepared using well-known and conventional techniques and materials readily available in the art. 6 WO 03/045305 PCT/USO2/36398 The shape and size of capsules can vary in accordance with the invention. In addition to the conventional oblong shape, the capsules can be in the form of a sphere, oval, tablet, and the like. The size of the capsule used will vary in accordance to the volume of the fill composition intended to be contained therein. 5 The active ingredient of the composition of the invention is acetaminophen and chemical derivatives thereof having equivalent pharmaceutical effect. The amount of acetaminophen used in the pharmaceutical composition will depend upon the amount of the drug desired to be administered in the dosage form while maintaining the solubility and clarity characteristics of the entire composition 10 including the solvent system. The invention includes a solvent system for acetaminophen which comprises an alkali metal lactate salt. In particular, preferred for use in the solvent system of the invention are alkali metal 1-lactate salts, such as sodium 1-lactate. In preparing compositions of the invention, the solvent system to be used can contain the 1-lactate 15 salt alone or, preferably, in combination with an alkali metal acetate salt. When the acetate salt is used, potassium acetate is preferred. Surprisingly, it has been discovered that not only are the desirable properties of the fill composition obtained by virtue of the particular number of carbon atoms in the carboxylate chain used in the solvent system, but also are affected by the specific rotational chemistry of the 20 carboxylate salt. In other words, not only are the best results obtained using lactate as compared to other carboxylate salts, but in particular 1-lactate (levo) as compared to racemic dl-lactate salts. The highest concentrations of acetaminophen per given total 7 WO 03/045305 PCT/USO2/36398 fill volume can be obtained using 1-lactate salt as the carboxylate salt. Alternatively and preferably, the concentration of acetaminophen per given fill vohune can be increased even more when the combination of 1-lactate and an acetate salt, such as potassium acetate, are used simultaneously. 5 The composition of the invention further includes within the solvent system polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP). In a preferred embodiment, the polyethylene glycol is polyethylene glycol 600 (available from Union Carbide, Danbury, CT). Suitable polyvinylpyrrolidone includes Povidone 25 (available from BASF, Mount Olive, NJ and ISP, Freetown, MA). 10 The amounts of each ingredient of the solvent system can vary slightly provided the solubility characteristics of acetaminophen and the desirable clarity of the overall fill composition are maintained. The lactate salt can generally be present in an amount ranging from about 4.0% to about 12.3% by weight of the fill composition. When present, the acetate salt can be present in an amount ranging from 15 about 4.0% to about 7.0% by weight of the fill composition. When both 1-lactate and acetate salts are used, the amount of 1-lactate can be lower relative to the use of 1 lactate alone in the solvent system. Polyethylene glycol can be present in an amount ranging from about 30.0% to about 40.0% by weight of the fill composition. Polyvinyl pyrrolidone can be present in an amount ranging from about 3.0% to about 20 7.0% by weight of the fill composition. In the interest of minimizing the overall fill volume while maximizing the concentration of the active ingredient, the use of additional ingredients is possible but 8 WO 03/045305 PCT/USO2/36398 not recommended. The invention offers the advantage of making available the administration of a given dosage amount of active ingredient using smaller capsule sizes, thereby increasing patient comfort and compliance, as well as reduced packaging and materials volume. The clarity of the pharmaceutical fill composition 5 provides a more appealing appearance and affords the ability to utilize visually appealing transparent capsule casing materials, as compared to compositions producing a cloudy or milky appearance. Pharmaceutical compositions of the invention can be prepared generally using the basic preparation steps of initially solubilizing polyvinyl pyrrolidone in 10 polyethylene glycol by mixing them together at a temperature of about 30' C for approximately 15 to 20 minutes until the polyvinyl pyrrolidone is completely solubilized. The active ingredient, acetaminophen, can then be added to the mixture at high speed for a period ranging from about 30 minutes to about 45 minutes. During the addition step of acetaminophen, the temperature of the mixture can be slowly 15 increased to about 650 C and maintained. The carboxylate salts, i.e., lactate or lactate and acetate, and water can then be added. The temperature of the mixture can bq increased to about 700 C. The mixture can be continuously stirred for a period ranging from about 1 hour to about 2 hours, while maintaining the temperature. Conventional capsule manufacturing techniques and equipment can be used to 20 prepare the composition-filled capsules of the invention. Typically, ribbon and die roller manufacturing techniques are suitable for preparation of the capsules of the invention. Encapsulation apparatuses such as that described in Stroud et al. U.S. 9 WO 03/045305 PCT/USO2/36398 Patent No. 5,735,105, the entire text of which is incorporated by reference herein, can be used. The following examples further illustrate aspects of the invention, and none of which are intended to be construed as limiting the invention. 5 EXAMPLES Preparation of Acetaminophen Formulations: A variety of formulations containing acetaminophen within different solvents and solvent compositions were compared. Each of the formulations was prepared by first mixing together polyethylene glycol (Polyethylene glycol 400 and 600) 10 (available from Union Carbide, Danbury, CT) with polyvinyl pyrrolidone (Povidone 25 available from BASF, Mount Olive, NJ and ISP, Freetown, MA) at 300 C for approximately 15 to 20 minutes until the polyvinyl pyrrolidone (Povidone 25) was completely solubilized in the polyethylene glycol. Acetaminophen was added to the mixture at high speed for about 30 to 45 minutes, during which time the temperature 15 of the mixture was slowly increased to 650 C and maintained. The salts and water were then added, and the temperature of the mixture was increased to 700 C. The mixture was continuously stirred for 1 to 2 hours. Clarity and crystallization observation was done throughout the final steps of mixing. Comparison of Acetamninophen Formulations (Lactate vs. Acetate Salts) 20 The following batch formulations were prepared in accordance with the above process: 10 WO 03/045305 PCT/USO2/36398 Formula 1 2 3 4 (239-140A) (239-101) (239-102) (239-108) % by weight/grams per batch Polyethylene glycol 0.0%/0 38.8%/38.88 39.8%/39.82 35.3%/35.27 600 Polyethylene glycol 36.3%/23.7 0.0%/0 0.0%/0 0.0%/0 400 Povidone 25 3.80//2.5 5.0%/5.0 5.0%/5.0 7.0%/7.0 Acetaminophen 39.9%/26.0 41.0%/41.0 41.0%/41.0 42.0%/42.0 Sodium 1-lactate 12.3%/8.0 8.2%/8.2 0.0%/0 4.7%/4.675 Potassium acetate 0.0%/0 0.0%/0 7.2%/7.18 4.1%/4.089 Water 7.7%/5.0 7.0%/7.0 7.0%/7.0 7.0%/7.0 Total 100.0%/65.2 100.0%/100.1 100.0%/100.0 100.1%/100.3 Total Fill Sample Volume 100.0 g = 83.3 ml Clarity Not clear Cloudy Cloudy Clear As can be seen from the above data, the results show that the combined advantage of highest concentration of solubilized acetaminophen and clarity (indicating the observable presence or absence of crystallization) occurred with 5 Formula 4, which contained the combination of sodium 1-lactate and potassium acetate salts in the solvent system. Some crystallization occurred with the separate use of sodium 1-lactate and potassium acetate, as seen from the results of Formulas 2 and 3. The combination of polyethylene glycol and only sodium 1-lactate also resulted in crystallization. 10 Comparison of Acetaminpohen Formulations Using Leverous vs. Racemic Lactate Salts: Two acetaminophen-containing batch compositions were prepared according to the process described above, the ingredients and relative amounts being as follows: 15 11 WO 03/045305 PCT/USO2/36398 Formula 5 6 (239-91A) (239-91B) % by weight /grams per batch Polyethylene glycol 400 36.3%/23.7 36.3%/23.7 Povidone 25 3.8%/2.5 3.8%/2.5 Acetaminophen 39.9%/26 39.9%/26 Sodium 1-lactate 12.3%/8.0 0.0%/0 Sodium dI-lactate 0.0%/0 12.3%/8.0 Water 7.7%/5.0 7.7%/5.0 Total 100.0%/65.2 100.0%/65.2 Total Fill Sample Volume 100.0g = 8.3 ml Clarity Clear Hazy As can be seen from the above data, acetaminophen-containing formulations using 1-lactate (leverous) exhibited clarity as compared to the dl-lactate (racemic) formulation. Observable crystallization occurred with the combination of 5 acetaminophen and the racemic lactate salt, whereas the formulation using sodium 1 lactate was clear. Comparison of Acetaminophen Formulations Using Longer Chain Carboxvlate Salts The following batch formulations were prepared using the process described above. Formula 7 8 9 (239-81) (239-85) (239-29) % by weight/grams per batch Polyethylene glycol 600 41.9%/106.0 49.5%/120.0 42.9%/480.0 Povidone 25 5.1%/13.0 5.2%/12.6 4.7%/52.9 Acetaminophen 32.1%/81.25 30.0%/72.7 29.1%/325.0 Propylene glycol 0.0%/0 0.0%/0 2.7%/30.0 Sodium propionate 11.0%/28.0 0.0%/0 0.0%/0 Sodium butyrate 0.0% 5.0%/12.0 0.0%/0 Sodium benzoate 0.0% 0.0% 7.3%/82.0 Water 9.9%/25.0 10.3%/25.0 13.2%/147.6 Total 100.0%/253.25 100.0%/242.3 99.9%/1 117.5 Total Fill Volume 100.0g = 83.3 ml Clarity Hazy Clear/odor Hazy 12 WO 03/045305 PCT/USO2/36398 Various formulations were prepared using longer chain carboxylate salts and results were observed. As can be seen, the formulations containing either sodium propionate or sodium benzoate and acetaminophen were hazy in appearance. Although the formulation containing sodium butyrate exhibited some clarity, an 5 objectionable pungent odor was present. Furthermore, the concentration of acetaminophen was not significantly improved using the butyrate salt. Other similar formulations using succinate, maleate and maleic acid were prepared. However, these formulations were not homogenous due to the lack of miscibility with polyethylene glycol. 10 As can be derived from the above results collectively, obtaining a collective balance between the desirable properties of increased solubility and avoiding crystallization while maintaining chemical compatibility amongst the various ingredients is surprisingly sensitive to relatively minor differences in the chemistry of the ingredients and their amounts. Even differences in the rotational nature of a 15 compound (e.g., levo versus racemic salts) produce different results. Industrial Applicability: The compositions according to the invention permit the use of effective doses of acetaminophen to be prepared using smaller capsule sizes. This significantly 20 reduces manufacturing costs and increases patient comfort. Furthermore, when transparent soft capsules are used for acetaminophen, the clarity and coloration of the inventive composition renders a more appealing final product. 13 WO 03/045305 PCT/USO2/36398 The invention has been described with reference to specific ingredients, ranges, techniques, and the like. It will be understood to one of ordinary skill that reasonable modifications and variations of the same are possible without departing 5 from the spirit or scope of the invention defined by the claims set forth hereinbelow. 14

Claims (17)

1. A pharmaceutical composition adapted for use in capsular dosage forms comprising: acetaminophen as an active ingredient and a solvent system comprising a lactate salt.

2. The pharmaceutical composition of claim 1 wherein the solvent system comprises 1-lactate.

3. The pharmaceutical composition of claim 2 wherein the 1-lactate is sodium 1 lactate.

4. The pharmaceutical composition of claim 2 wherein the solvent system of the composition further comprises an alkali metal acetate salt.

5. The pharmaceutical composition of claim 4 wherein the alkali metal acetate salt is potassium acetate.

6. The pharmaceutical composition of claim 1 wherein the solvent system further comprises polyethylene glycol and polyvinyl pyrrolidone.

7. A pharmaceutical composition comprising: acetaminophen in an amount of at least about 40% by weight; sodium 1-lactate in an amount of at least about 4.0% by weight; and potassium acetate in an amount of at least about 4.0% by weight.

8. The pharmaceutical composition of claim 7 wherein said acetaminophen is present in an amount of about 42% by weight. 15 WO 03/045305 PCT/US02/36398

9. A capsular dosage form containing a pharmaceutical composition comprising: acetaminophen as an active ingredient and a solvent system comprising an alkali metal lactate salt.

10. The capsular dosage form of claim 9 wherein the lactate salt of the solvent system is 1-lactate.

11. The capsular dosage form of claim 10 wherein the 1-lactate salt is sodium 1 lactate.

12. The capsular dosage form of claim 9 wherein the solvent system of the composition further comprises an alkali metal acetate salt.

13. The capsular dosage form of claim 12 wherein the alkali metal acetate salt is potassium acetate.

14. The capsular dosage form of claim 9 wherein the solvent system of the composition further comprises polyethylene glycol and polyvinyl pyrrolidone.

15. The capsular dosage form of claim 9 wherein the composition comprises the following formula: acetaminophen in an amount of at least about 40% by weight; sodium 1-lactate in an amount of at least about 4.0% by weight; and potassium acetate in an amount of at least about 4.0% by weight.

16. The capsular dosage form of claim 15 wherein acetaminophen is present in an amount of about 42% by weight.

17. The capsular dosage form of claim 9 wherein the capsular material comprises gelatin. 16